Cited by 851Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Diagnosis and Treatment

The DOI matches its Crossref record; 13 of the 23 references it cites were found in a registry or an index, and 10 are not checked yet; none of the 18 sources its claims cite is checked for support yet.

Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer

Open access

Abstract

Purpose: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. Methods: Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients. Results: Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). Conclusion: In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M.

Checked 2026-10-06 · 10 references not checked yet

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective analysis of the phase I AURA trial, patients with T790M detected in plasma by BEAMing had osimertinib outcomes similar to those with T790M detected in tumor tissue. Because plasma genotyping had a 30% false-negative rate for T790M, patients with T790M-negative plasma still needed tumor biopsy to determine T790M status.

Key findings

  • Plasma genotyping sensitivity was 70% for T790M (111 of 158; 95% CI, 63% to 77%), 82% for exon 19 deletion (112 of 136; 95% CI, 75% to 88%), and 86% for L858R (63 of 73; 95% CI, 76% to 93%).
  • Of 58 patients with T790M-negative tumors, T790M was detected in plasma in 18 (31%); repeat testing with an alternative plasma assay confirmed T790M in 14 of 18 (78%).
  • ORR and median PFS were similar for T790M-positive plasma (ORR, 63%; PFS, 9.7 months) and T790M-positive tumor (ORR, 62%; PFS, 9.7 months).
  • Among patients with T790M-negative plasma, tumor genotyping distinguished T790M-positive tumors (ORR, 69%; PFS, 16.5 months) from T790M-negative tumors (ORR, 25%; PFS, 2.8 months).

Methods

  • Post hoc/exploratory analysis of the phase I AURA study of osimertinib in advanced EGFR-mutant NSCLC; 402 patients enrolled, 60 first-line patients excluded, 34 without a common EGFR-sensitizing mutation excluded, leaving 308 patients.
  • Plasma cfDNA was collected before osimertinib and genotyped by BEAMing for T790M, L858R, and exon 19 deletion variants; positivity thresholds were ≥ 0.04% allelic fraction for exon 19 deletion or L858R and ≥ 0.06% for T790M; discordant plasma/tumor T790M results were retested with cobas plasma EGFR assay or ddPCR.
  • Outcomes included confirmed ORR, maximum change in target lesion size, and PFS by RECIST version 1.1 per investigator; analyses used Clopper-Pearson exact CIs, Fisher’s exact or χ2 tests, and Kaplan-Meier estimates with log-rank tests.

Limitations

  • The paper states the analysis was not preplanned, the study population was not fully representative of all acquired EGFR-TKI resistance because of intentional enrichment for T790M-positive patients, BEAMing was not performed under Clinical Laboratory Improvement Amendments conditions, and prospective validation is needed.
  • Evident from the text: this was a retrospective post hoc analysis, and some key subgroups were small, such as the 18 patients with T790M-positive plasma but T790M-negative tumor genotyping.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1200/jco.2016.66.7162

Cites

13 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 18 cited sources checked · 0 supported · 0 flagged

Show all 47 claims

  • It may state two separate claims as one. 21
  • Probably not a substantial claim. 8
26 of 26
  • The paper relies on this without support.

    Resistant cancers are inherently more heterogeneous than treatment-naïve cancers.

    “Resistant cancers are inherently more heterogeneous than treatment-naïve cancers and, therefore, a single tumor biopsy may not be representative of the entire resistant cancer.”
  • The paper relies on this without support.

    The BEAMing assay has negligible false positives for T790M.

    “We found that 31% of patients who are negative for T790M on central tumor genotyping have detectable T790M in plasma with a BEAMing assay that otherwise has negligible false positives, though the relative AF of plasma T790M is lower in these patients than in patients with T790M-positive plasma and tumors.”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Different median PFS values for the same subgroup

    Minor

    For patients with T790M-negative plasma but T790M-positive tumors, the Results report a median PFS of 16.5 months, while the Discussion reports 16.2 months.

  • Response-evaluable count presented as the plasma-positive cohort size

    Minor

    The Results say that 164 of the 271 plasma-genotyped patients were T790M positive, but Table A1 lists 167. The 164 figure is the denominator used for ORR, not the tabulated size of the plasma-positive cohort.

  • Incorrect percentage for the 80 mg tumor-genotyping subgroup

    Minor

    Table A1 reports 90 patients at 80 mg among 237 patients with central tumor genotyping. That is 38.0%, not 40.0%.

    Reported 40 · recomputed 37.974684

3 of 3

Citations

Cites

Flagged first, then by citations

Show all 23 references

Cited by

Sorted by citations

Items 501–600 of 851

Metadata

Authors
Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., Yang, J. C.-H., Barrett, J. C., & Jänne, P. A.
Affiliations
  • National Taiwan University (TW)
  • Geoffrey R. Oxnard, Ryan S. Alden, Cloud P. Paweletz, and Pasi A. Jänne, Dana-Farber Cancer Institute, Boston; Kenneth S. Thress and J. Carl Barrett, AstraZeneca, Waltham, MA; Rachael Lawrance and Mireille Cantarini, AstraZeneca, Macclesfield, United Kingdom; and James Chih-Hsin Yang, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
Venue
Journal of Clinical Oncology
Published
2016-10-01
Volume
34
Issue
28
Pages
3375-3382
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
OpenAlex
W2468983064
Cited by
850
References
23
Citations by year
2026: 23 · 2025: 21 · 2024: 35 · 2023: 61 · 2022: 66 · 2021: 105 · 2020: 99 · 2019: 120 · 2018: 151 · 2017: 149 · 2016: 18
FWCI
130.49
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • AstraZeneca
  • National Institutes of Health
  • National Cancer Institute (R01CA135257, U01CA210171)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords
osimertinib, T790M mutation, liquid biopsy, plasma cell-free DNA, beaming, EGFR tyrosine kinase inhibitors, non-small cell lung cancer, treatment response prediction, false negative rate, tumor biopsy, progression-free survival, objective response rate, first-in-man trial
MeSH terms
Acrylamides, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA, Neoplasm, Genotype, Humans, Indoles, Lung Neoplasms, Piperazines, Pyrimidines, Retrospective Studies, Biomarkers, Tumor, Treatment Outcome, Disease-Free Survival, Protein Kinase Inhibitors, Kaplan-Meier Estimate, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review